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Cell-cell adhesions are critical to the development and maintenance of multicellular organisms. Increased tyrosine phosphorylation of junctional proteins has been associated with promoting disassembly of protein complexes at junctions and reducing cell-cell adhesions. Levels of tyrosine phosphorylation reflect the balance between protein-tyrosine kinase (PTK) and protein-tyrosine phosphatase (PTP) activity. DEP-1 is a receptor PTP which localizes to cell-cell adhesions and has been implicated in regulating phosphorylation of junctional proteins. The catalytically dead substrate-trapping mutant of DEP-1 (DEP-1 D/A) was used to identify additional substrates at cell-cell junctions. Members of the tight junction, occludin and ZO-1, were found to be substrates of DEP-1. DEP-1 D/A was not only able to bind these proteins in a tyrosine-phosphorylation dependent manner but wild type DEP-1 was able to dephosphorylate them. Occludin and ZO-1 interactions with DEP-1 were mediated through binding to the catalytic domain of DEP-1 and not by other protein-protein interaction motifs examined and appear to be specific to DEP-1. Over-expression of DEP-1 increased transepithelial electrical resistance in confluent epithelial monolayers and also reduced paracellular flux of FITC-dextran following a calcium switch. In addition, FAK and paxillin were also identified to be substrates of DEP-1 and indicate that DEP-1 could be regulating integrin adhesion-mediated signaling as well. Future work will focus on mapping the occludin residues necessary for DEP-1 interaction and will help to clarify potential signaling pathways and kinases upstream of DEP-1 activity. By controlling phosphotyrosine levels of tight junction proteins and perhaps focal adhesion proteins, DEP-1 may play a role in regulating permeability and junction formation in epithelial cells.

Cell-cell adhesion is critical to the development and maintenance of multicellular organisms. The stability of many adhesions is regulated by protein tyrosine phosphorylation of cell adhesion molecules and their associated components, with high levels of phosphorylation promoting disassembly. The level of tyrosine phosphorylation reflects the balance between protein-tyrosine kinase and protein-tyrosine phosphatase activity. Many protein-tyrosine phosphatases associate with the cadherin-catenin complex, directly regulating the phosphorylation of these proteins, thereby affecting their interactions and the integrity of cell-cell junctions. Tyrosine phosphatases can also affect cell-cell adhesions indirectly by regulating the signaling pathways that control the activities of Rho family G proteins. In addition, receptor-type tyrosine phosphatases can mediate outside-in signaling through both ligand binding and dimerization of their extracellular domains. This review will discuss the role of protein-tyrosine phosphatases in cell-cell interactions, with an emphasis on cadherin-mediated adhesions.